This is a request for 5 years of support through the K01 Mentored Research Scientist Development Award mechanism. The Candidate, a behavioral neuroscientist with experience using a preclinical rodent model of cocaine addiction, proposes a clinical research training program at McLean Hospital that combines extensive learning experience in several neuroimaging methods and in neuropsychological and self-report assessments, in a nicotine-dependent population. The program includes 1-on-1 expert mentorship, coursework in MR technology, data processing and analysis strategies, attendance and presentations at drug dependence and brain imaging scientific conferences, participation in psychiatric and neuroscience seminars, and ongoing Responsible Conduct of Research training. Skills acquired through these training opportunities will be implemented and honed through the application's research component. As adult smokers exhibit a number of structural, functional/cognitive and neurochemical changes that may result directly from early smoking, this will be the focus of the research plan. Specifically, the proposed studies will fulfill a short-ter career goal of integrating multimodal neuroimaging and neuropsychological and self-report assessments to develop a biological and cognitive profile of early- (<16 yrs. old) vs. late-onset (? 16 yrs. old) nicotine-dependent adults. To this end, the effects of early- vs. late-onset smoking on the neurobiology and cognitive performance of adult smokers will be investigated by 3 independent research aims. First, the applicant will apply EEG/ERP technology, physiological activity, and self-reported ratings of craving to measure increased smoking cue reactivity and craving during withdrawal conditions. Second, the applicant will learn phosphorus magnetic resonance spectroscopy [31P MRS] methods and to conduct neuropsychological assessments of multiple cognitive domains (i.e. attention, working memory, impulsivity) to assess alterations in bioenergetic and phospholipid neurometabolite levels and cognitive processing measured during acute nicotine administration and withdrawal conditions. Third, the applicant will learn how to apply diffusion tensor imaging (DTI) methods to measure altered white matter structure between groups. Collectively, the empirical evidence of adult neural alterations and cognitive deficits resulting from early-onset smoking may be used to predict if certain treatment approaches should be applied differentially too late- vs. early-onset smokers to improve smoking cessation outcomes. Overall, the proposed training and research projects will confer detailed knowledge and training in the theory and implementation of multiple neuroimaging techniques as well as in optimal study design, study management, and data analysis and interpretation. The Candidate will therefore acquire the research skills and tools necessary to transition into a long-term career goal of making meaningful contributions towards understanding the neurobiological etiology and cognitive sequel of addiction by integrating multimodal brain imaging and neuropsychological techniques as an innovative and versatile independent investigator. PUBLIC HEALTH RELEVANCE: Adolescent tobacco use remains the largest threat to public health, as early exposure (< 16 years old) to nicotine may uniquely disrupt neuromaturational development relative to those with a later onset of smoking (> 16 years old). Using multimodal imaging approaches to examine the impact of age of onset of nicotine use will clarify whether early exposure to nicotine results in greater structural, cognitive and neurochemical alterations relative to those who begin smoking later. Evidence of neural alterations and cognitive deficits resulting from early onset smoking will provide critical information regarding which specific treatment approaches should be applied to early vs. late onset smokers, which is likely to improve smoking cessation outcomes.